Our overall objective is to evaluate the association between chronic periodontal disease and incidence of cardiovascular disease, and to prospectively assess the role of inflammatory biomarkers in this association. Results from our epidemiologic studies among men show associations between periodontal disease and increased risk of (a) peripheral arterial disease (PAD) and (b) ischemic stroke. The proposed study will be conducted among male and female participants of two ongoing prospective studies: Health Professionals' Follow-up Study with over 50,000 men, and Nurses' Health Study with over 100,000 women. Our prospective study in the same populations and several other studies are already funded to evaluate the association between periodontal disease, inflammatory markers and coronary heart disease. Hence we limit this proposal to evaluating the association between periodontal bone loss and ischemic stroke and PAD. We have demonstrated associations between periodontal disease and pro-inflammatory cytokines, markers of inflammation, and endothelial dysfunction in these cohorts. We will evaluate prospectively the relationship between standard measures of periodontal disease and incidence of PAD and ischemic stroke, and evaluate whether markers of inflammation and endothelial dysfunction may mediate the association between periodontal disease and ischemic stroke and PAD. This will be the first study to evaluate the relationship between periodontal disease and PAD among women, and among the first studies to prospectively evaluate inflammatory mediators in the pathway between periodontal disease and cardiovascular disease. We will include all incident cases and two matched controls per case, from the subgroup who already provided blood samples, and obtain their pre-existing radiographs from their dentists after requesting these participant's consets. The biochemical marker analyses will be conducted from the blood samples participants for whom we obtain dental radiographs. Ischemic stroke and PAD will be verified from medical records. We anticipate 500 eligible cases of ischemic stroke and 500 PAD cases and 2 matched controls per case, with a total sample size of 3,000. Since periodontal disease is very common, if it is found to increase the risk of CVD, millions of people may be impacted. The results from this study may suggest possibilities for prevention of CVD that would need to be further explored.